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Mukwaya, Anthony
Publications (6 of 6) Show all publications
Mukwaya, A. (2018). Regulation of inflammation and angiogenesis in the cornea. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Regulation of inflammation and angiogenesis in the cornea
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammation and angiogenesis, the growth of new blood vessels from pre-existing ones, are involved in tumor growth, ocular diseases and wound healing. In ocular angiogenesis, new pathological vessels grow into a specific eye tissue, leak fluid, and disrupt vision. The development of safe and effective therapies for ocular angiogenesis is of great importance for preventing blindness, given that current treatments have limited efficacy or are associated with undesirable side effects. The search for alternative treatment targets requires a deeper understanding of inflammation and how it can lead to angiogenesis in the eye in pathologic situations. This thesis provides new insights into the regulation of inflammation and angiogenesis, particularly at the gene expression and phenotypic levels, in different situations characterized by angiogenesis of the cornea, often called corneal neovascularization. For instance, specific genes and pathways are either endogenously activated or suppressed during active inflammation, wound healing, and during resolution of inflammation and angiogenesis, serving as potential targets to modulate the inflammatory and angiogenic response. In addition, as part of the healing response to restore corneal transparency, inflammation and angiogenesis subside with time in the cornea. In this context, LXR/RXR signaling was found to be activated in a time-dependent manner, to potentially regulate resolution of inflammation and angiogenesis. During regression of new angiogenic capillaries, ghost vessels and empty basement membrane sleeves are formed, which can persist in the cornea for a long time. Here, ghost vessels were found to facilitate subsequent revascularization of the cornea, while empty basement membrane sleeves did not revascularize. The revascularization response observed here was characterised by vasodilation, increased inflammatory cell infiltration and by sprouting at the front of the reperfused vessels. Importantly, reactive oxygen species and nitrous oxide signaling among other pro-inflammatory pathways were activated, and at the same time anti-inflammatory LXR/RXR signaling was inhibited. The interplay between activation and inhibition of these pathways highlights potential mechanisms that regulate corneal revascularization. When treating corneal neovascularization clinically, corticosteroids are in widespread use due to their effectiveness. To minimize the many undesirable side effects associated with corticosteroid use, however, identifying new and more selective agents is of great importance. Here, it was observed that corticosteroids not only suppressed pro-inflammatory chemokines and cytokines, but also activated the classical complement pathway. Classical complement may represent a candidate for further selective therapeutic manipulation to investigate its effect on treatment of corneal neovascularization.

In summary, this thesis identifies genes, pathways, and phenotypic responses involved in sprouting and remodeling of corneal capillaries, highlights novel pathways and factors that may regulate inflammation and angiogenesis in the cornea, and provides insights into regulation of capillary regression and reactivation. Further investigation of these regulatory mechanisms may offer alternative and effective treatment targets for the treatment of corneal inflammation and angiogenesis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 55
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1625
National Category
Ophthalmology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-147979 (URN)10.3384/diss.diva-147979 (DOI)9789176852842 (ISBN)
Public defence
2018-06-01, Nils-Holger salen, Campus US, Linköping, 13:06 (English)
Opponent
Supervisors
Available from: 2018-05-21 Created: 2018-05-21 Last updated: 2019-09-30Bibliographically approved
Lennikov, A., Mirabelli, P., Mukwaya, A., Schaupper, M., Thangavelu, M., Lachota, M., . . . Lagali, N. (2018). Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis. Angiogenesis, 21(2), 267-285
Open this publication in new window or tab >>Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
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2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 2, p. 267-285Article in journal (Refereed) Published
Abstract [en]

Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.

Place, publisher, year, edition, pages
Springer Netherlands, 2018
Keywords
Cornea; Neovascularization; NF-kappa B; IMD0354; IKK2; VEGF
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-147373 (URN)10.1007/s10456-018-9594-9 (DOI)000428924500007 ()29332242 (PubMedID)2-s2.0-85041334437 (Scopus ID)
Note

Funding Agencies|Swedish Research Council [2012-2472]; Swedish Foundation Stiftelsen Synframjandets Forskningsfond/Ogonfonden; Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Jeanssons Stiftelser

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2019-05-01Bibliographically approved
Mukwaya, A., Lennikov, A., Xeroudaki, M., Mirabelli, P., Lachota, M., Jensen, L., . . . Lagali, N. (2018). Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization. Angiogenesis, 21(2), 395-413
Open this publication in new window or tab >>Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization
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2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 2, p. 395-413Article in journal (Refereed) Published
Abstract [en]

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPAR alpha/RXR alpha and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/beta-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1 beta, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPAR alpha/RXR alpha and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.

Place, publisher, year, edition, pages
Springer Netherlands, 2018
Keywords
Cornea neovascularization; Inflammation; Angiogenesis; Remodeling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-147374 (URN)10.1007/s10456-018-9604-y (DOI)000428924500016 ()29445990 (PubMedID)2-s2.0-85042119664 (Scopus ID)
Note

Funding Agencies|Swedish Research Council [2012-2472]

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-08-02Bibliographically approved
Mukwaya, A., Mirabelli, P., Lennikov, A., Xeroudaki, M., Schaupper, M., Peebo, B. & Lagali, N. (2017). Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea. Scientific Data, 4, Article ID 170111.
Open this publication in new window or tab >>Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea
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2017 (English)In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170111Article in journal (Refereed) Published
Abstract [en]

Therapeutics against pathologic new blood vessel growth, particularly those targeting vascular endothelial growth factor (VEGF) are of enormous clinical interest. In the eye, where anti-VEGF agents are in widespread clinical use for treating retinal and corneal blindness, only partial or transient efficacy and resistance to anti-VEGF agents are among the major drawbacks. Conversely, corticosteroids have long been used in ophthalmology for their potency in suppressing inflammation and angiogenesis, but their broad biological activity can give rise to side effects such as glaucoma and cataract. To aid in the search for more targeted and effective anti-angiogenic therapies in the eye, we present here a dataset comparing gene expression changes in dexamethasone versus anti-Vegfa treatment of inflammation leading to angiogenesis in the rat cornea. Global gene expression analysis with GeneChip Rat 230 2.0 microarrays was conducted and the metadata submitted to Expression Omnibus repository. Here, we present a high-quality validated dataset enabling genome-wide comparison of genes differentially targeted by dexamethasone and anti-Vegf treatments, to identify potential alternative therapeutic targets for evaluation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Ophthalmology Medical Genetics
Identifiers
urn:nbn:se:liu:diva-140046 (URN)10.1038/sdata.2017.111 (DOI)000407551900002 ()
Note

Funding Agencies|Swedish Research Council [2012- 2472]; Swedish Ophthalmological Society Stiftelsen Synframjandets Forskningsfond/Ogonfonden

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2019-02-11Bibliographically approved
Mirabelli, P., Mukwaya, A., Lennikov, A., Xeroudaki, M., Peebo, B., Schaupper, M. & Lagali, N. (2017). Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea. Scientific Reports, 7, Article ID 7616.
Open this publication in new window or tab >>Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7616Article in journal (Refereed) Published
Abstract [en]

Angiogenesis as a pathological process in the eye can lead to blindness. In the cornea, suppression of angiogenesis by anti-VEGF treatment is only partially effective while steroids, although effective in treating inflammation and angiogenesis, have broad activity leading to undesirable side effects. In this study, genome-wide expression was investigated in a suture-induced corneal neovascularization model in rats, to investigate factors differentially targeted by dexamethasone and anti-Vegf. Topical treatment with either rat-specific anti-Vegf, dexamethasone, or normal goat IgG (sham) was given to sutured corneas for 48 hours, after which in vivo imaging, tissue processing for RNA microarray, and immunofluorescence were performed. Dexamethasone suppressed limbal vasodilation (P amp;lt; 0.01) and genes in PI3K-Akt, focal adhesion, and chemokine signaling pathways more effectively than anti-Vegf. The most differentially expressed genes were confirmed by immunofluorescence, qRTPCR and Western blot. Strong suppression of Reg3g and the inflammatory chemokines Ccl2 and Cxcl5 and activation of classical complement pathway factors C1r, C1s, C2, and C3 occurred with dexamethasone treatment, effects absent with anti-Vegf treatment. The genome-wide results obtained in this study provide numerous potential targets for specific blockade of inflammation and angiogenesis in the cornea not addressed by anti-Vegf treatment, as possible alternatives to broad-acting immunosuppressive therapy.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-140047 (URN)10.1038/s41598-017-07129-4 (DOI)000407569300001 ()28811496 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-2472]; Swedish Foundation Stiftelsen Synframjandets Forskningsfond/Ogonfonden

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2019-04-18
Harada, F., Morikawa, T., Lennikov, A., Mukwaya, A., Schaupper, M., Uehara, O., . . . Kitaichi, N. (2017). Protective Effects of Oral Astaxanthin Nanopowder against Ultraviolet-Induced Photokeratitis in Mice. Oxidative Medicine and Cellular Longevity, Article ID 1956104.
Open this publication in new window or tab >>Protective Effects of Oral Astaxanthin Nanopowder against Ultraviolet-Induced Photokeratitis in Mice
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2017 (English)In: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, article id 1956104Article in journal (Refereed) Published
Abstract [en]

Purpose. Astaxanthin (AST) has a strong antioxidant cellular membrane chaperone protective effect. Recently, a water-soluble nanosized AST (nano-AST) form was produced, which is expected to improve the efficacy of oral intake effects. The purpose of this study was to examine whether oral nano-AST has therapeutic effects on UV-induced photokeratitis in mice. Methods. C57BL/6 mice were administered twice with either nano-AST, AST oil, lutein, or bilberry extracts 3 hours before and shortly before UV irradiation (dose: 400 mJ/cm2). The corneas were collected 24 hours after irradiation and stained with Hamp;E and TUNEL. NF-kappa B, dihydroethidium (DHE), COX-2, p-I kappa B-alpha, TNF alpha, and CD45 expression were evaluated through immunohistochemistry, Western blot analysis, and qPCR. Results. Corneal epithelium was significantly thicker in mice orally administered with nano-AST than in the others (p amp;lt; 0.01), with significantly less NF-kappa B nucleus translocation (p amp;lt; 0.001), and significantly fewer TUNEL cells (p amp;lt; 0.01). Weaker DHE signals were detected in the nano-AST group (p amp;lt; 0.05) relative to the others. Furthermore, reduced inflammation and decreased cell death in corneal tissue were observed in the nano-AST group, as indicated by a reduction in the expression of COX-2, p-I kappa B-alpha, TNFa, and CD45. Conclusions. Oral administration of nano-AST demonstrated a protective effect on UV-induced photokeratitis via antioxidative, anti-inflammatory, and antiapoptotic activity.

Place, publisher, year, edition, pages
HINDAWI LTD, 2017
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-141943 (URN)10.1155/2017/1956104 (DOI)000411941700001 ()
Note

Funding Agencies|FUJIFILM Inc.; FUJIFILM Corporation

Available from: 2017-10-13 Created: 2017-10-13 Last updated: 2018-09-05
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